Electrical signals recorded from neurons by intracortical electrodes have been used by human patients to communicate with computers and to control robotic limbs. The signal quality and longevity of recordable signals are inconsistent. There is increasing evidence indicating that the neuro-inflammatory response may be a primary hurdle to consistently obtaining high quality recordings. Within the brain, cells are living in the elastic extracellular matrix (ECM) meshwork with 3D and high aspect ratio fibrillary protein structures. This environment is textured and compliant, not smooth or stiff. In contrast, to the currently accepted and used surfaces of intracortical microelectrodes. The discontinuity between the architecture and stiffness of the tissue and device results in the initial inflammatory and chronic foreign body response to the implant. Current research aimed at alleviating the inflammatory response, as well as improving the neuronal signal from electrodes, focuses on either therapeutic or materials-based solutions. Limited emphasis has been placed on combinatorial approaches that mimic the physical properties of the native ECM, including the architecture and stiffness. The current proposal seeks to progress the training of Dr. Ereifej where the CDA-1 training left off, ensuring continuity. The candidates CDA-1 preliminary work has successfully etched surface modifications based on the architecture (but not orientation) of native brain tissue onto non-functional silicon Michigan style shanks. It was shown that implants etched with nanoscale surface modifications were able to decrease glial cell activation and increase neuronal viability around the implant site over time. However, Dr. Ereifej has yet to: 1) characterize the long-term effects or 2) evaluate various orientations of lines, to determine the optimal surface modifications. Given the documented role that substrate stiffness has on cellular response to materials, it is also imperative to evaluate the configurations on materials with a modulus similar to brain tissue. Therefore, the central hypothesis to this proposal is that microelectrodes that more closely mimic the architecture and modulus of native brain tissue will result in improved biocompatibility, displayed through a reduced chronic inflammatory response, improved long-term recording stability, and decreased motor deficits. We propose to first characterize the neuroinflammatory, electrophysiological and motor behavior response evoked by chronic implantation of intracortical microelectrodes etched with surface modifications. This aim will test the hypothesis that microelectrodes etched with surface modifications mimicking that of the native environment will result in a reduced neuroinflammatory response of the surrounding tissue, improved stability of recorded neuronal signals and result in less motor deficits compared to control animals. Specific Aim 1 will utilize the neural implants with the bio-inspired surface architectures developed during the CDA-1 phase and therefore are available for immediate testing in vivo. Next, we will characterize the combined effects topographically- modified substrates displaying both bio-mimetic architecture and modulus. Here we will test the hypothesis that combination of topographical-modified substrates displaying both bio-mimetic architecture and modulus will result in a reduced inflammatory response compared to either modifications in isolation or control. Functional microelectrodes are not yet developed with all possible combinations of both architecture and modulus. Thus, SA2 will begin with modified PDMS and silicon substrates, and all testing will be completed in vitro. Together, SA1 and SA2 will provide the critical foundation to begin to explore the central hypothesis for this award. Most importantly, the CDA-2 mechanism will be utilized as designed, to provide a platform to establish a niche for Dr. Ereifej?s future independent research program. A Merit Review application is anticipated to be submitted to advance the findings from this CDA-2. This research is integrated with Evon Ereifej?s career development plan with the goal of training to become a leading investigator, studying nervous system diseases, injuries, and disorders to find therapeutic and medical device treatments to aid in the wellbeing and longevity of patients? lives.